DESCRIPTION: The investigator has previously provided evidence that cholecystokinin at physiologic levels acts on CCK-A receptors on vagal afferent nerve branches to mediate pancreatic secretion in rats. Interestingly, the effect of CCK is blocked by truncal vagotomy yet, over time, returns to basal. The primary focus of the current application is to examine the adaptive changes that are responsible for the post vagotomy phenomenon. It is proposed that adaptive changes occur in the enteric neural circuit and involve regulation of CCK receptors on enteric cholinergic neurons which stimulate pancreatic secretion via relay to intrapancreatic gastrin releasing peptide neurons. To investigate this novel neural pathway the PI will employ a variety of experimental techniques including antegrade tracing, immunohistochemistry, measurements of neurotransmitter release and electrophysiological studies. In addition, he will also examine changes in pancreatic acini that occur with vagotomy to determine the end organ response. The PI hypothesizes that antidromic release of CGRP following vagal CCK receptor activation stimulates secretion of somatostatin from the myenteric plexus which, in turn, exerts a tonic inhibition on expression or function of CCK receptors located on enteric cholinergic neurons projecting to the pancreas. Following chronic vagotomy the absence of antidromic release of CGRP results in little or no stimulation of somatostatin containing neurons thus resulting in enhanced expression or function of CCK receptors. Consequently, activation if GRP neuropathways located in the pancreas takes place which mediates pancreatic secretion. To ultimately establish the physiological significance of these proposed mechanisms, in vivo studies employing targeted duodenal administration of CGRP and somatostatin will be performed. Conversely, local duodenal administration of CGRP or somatostatin will be conducted in chronic vagotomized rats to prevent the development of adaptive changes.